Development of 3D Micro-scale Engineered Tissue Model Systems for Drug Discovery and development is a lengthy and expensive process. Recent surveys indicate that the average new drug taken to market in the United States requires 10 to 15 years of research and $300 million of investment. Drug discovery and development has benefited from new technology such as high- throughput screening methods for identifying lead compounds. However, the use of animal models for drug tests has caused inaccuracies and high cost to predict human responses, safety, and efficacy. A solution to this problem is the development of 3D engineered tissue model systems that closely mimic the complex environment and interaction of human organ systems. Despite their usefulness in drug discovery and development, currently available micro-scale engineered tissue model devices are all silicon based, with micro well and chamber like structures. During culture, cells tend to line on the walls of these structures to form 2D or 2=D aggregates, which may not have normal 3D tissue architecture to perform tissue specific functions. The goal of the proposed research is to develop an innovative fabrication method to create 3D micro- scale engineered tissue model systems for drug discovery. The proposed method combines selective foaming and micro milling to produce polymeric biochips with localized porous microstructures that are connected with microfluidic channels to emulate the biological environment of human tissue and organs. The porous microstructures allow 3D culture of cells such that tissue specific architecture and function can be maintained. With the fabricated tissue model systems, biological studies are also proposed on drug resistance, stromal-epithelial cell interaction, and liver metabolism effect on cancer chemotherapy drugs. The proposed research will bridge the gap in the state-of-the-art fabrication capabilities for microfluidic devices and 3D tissue engineering scaffolds. The engineered tissue model systems proposed in this research will have wide applications in drug discovery and development, as well as in basic and clinical research.